The efficacy of NMDA receptor antagonists in neuropsychiatric and non-motor symptoms of Parkinson’s disease: a systematic review

Abstract

ABSTRACT. Parkinson’s disease (PD) involves significant non-motor symptoms (NMS) linked to glutamate dysregulation. Objective: This review evaluates the efficacy of N-methyl-D-aspartate (NMDA) receptor antagonists (memantine and amantadine) for treating NMS. Methods: A search was conducted in the databases PubMed and Cochrane Library (January 2000–September 2025) for controlled trials focusing on NMS in idiopathic PD. Two reviewers assessed bias using Cochrane RoB 2. Results: Of 529 records, ten studies were included. Most exhibited a high risk of bias and heterogeneity. Memantine results were mixed: improvements in attention and behavioral symptoms were observed in PD dementia, but no benefit or worsened memory occurred in mild cognitive impairment. Memantine was beneficial for REM sleep behavior disorder. Extended-release amantadine improved sleepiness and mood but increased hallucinations and cognitive impairment. Conclusion: Evidence is limited by methodological flaws. While memantine offers selective benefits for PD dementia, amantadine carries notable cognitive risks. High-quality trials are essential to clarify therapeutic roles.